Expert Critique

Prior to the emergence of direct-acting antivirals (DAAs), treatment strategies for patients with decompensated cirrhosis in the setting of chronic hepatitis C virus (HCV) were substantially restricted. The key limitations of interferon-based therapy in this patient population included both an overall reduction in treatment efficacy as well as a large number of dose-dependent side effects, including but not limited to anemia and neutropenia.

As discussed in the article, DAAs have now changed the treatment paradigm by facilitating an option beyond simply liver transplantation or palliative care in HCV patients with decompensated cirrhosis. Among currently available DAAs, pharmacologic therapy may be tailored to the underlying HCV genotype as guided by the recent AASLD/IDSA guidelines.

While the outlook of DAA therapy is positive, HCV cure rates among patients with advanced liver disease have been observed to be lower than their healthier counterparts, and only those patients with acceptable life expectancies should be considered to be candidates for treatment.

Full Critique

Treatment using direct-acting antivirals (DAAs) produces good cure rates in chronic hepatitis C (HCV) patients with decompensated liver disease, offering new options for a group that often could not be treated with interferon-based therapy. Successful treatment can slow liver disease progression and may restore lost hepatic function.

In an interview with MedPage Today, Raymond Chung, MD, chief of Hepatology at Massachusetts General Hospital in Boston, elaborated on this topic, noting that people with decompensated cirrhosis can be treated using some of the same DAA combinations as those with less advanced disease, but they may need to add ribavirin or lengthen the duration of therapy.

On the other hand, this population is more likely to experience adverse events during treatment, including drug side effects and worsening liver function.

"First and foremost, because patients with decompensated cirrhosis are at high risk for life-threatening complications, these patients are best managed at centers with expertise in liver transplantation," he said.

Over years or decades, chronic hepatitis C virus infection can cause liver damage leading to end-stage liver disease, liver failure, and the need for a liver transplant. Up to 20% of people with chronic HCV develop cirrhosis, and of these, about 5% progress to decompensation annually.

As cirrhosis progresses, accumulating scar tissue interferes with blood flow through the liver, resulting in portal hypertension and signs of decompensation such as bleeding esophageal varices and ascites. Reduced synthetic function can lead to abnormalities in albumin and clotting factors, and the buildup of toxins can cause hepatic encephalopathy.

Chung noted that during the interferon era many patients with decompensated cirrhosis could not tolerate hepatitis C treatment, and pegylated interferon plus ribavirin has poor efficacy in this population. Because of that, many experts considered decompensation to be a contraindication for treatment, leaving palliative care and liver transplantation as the only options.

But the advent of direct-acting antivirals (DAAs) has changed the picture, Chung explained: Today, HCV treatment is contraindicated only for patients with very advanced liver failure, for whom organ function is unlikely to recover even if HCV infection is cured, and for those with a short life expectancy for other reasons.

Chung, a co-chair of the AASLD/IDSA guidelines panel, explained that patients with decompensated liver disease are classified as Child-Pugh Class B or C, based on a set of liver function biomarkers and symptoms. The Model for End-Stage Liver Disease (MELD) scoring system is used to prioritize candidates for liver transplantation, with mortality risk increasing steeply at scores above 19.

For decompensated patients with HCV genotypes 1 or 4, the AASLD/IDSA guidelines recommend use of sofosbuvir/ledipasvir (Harvoni), sofosbuvir/velpatasvir (Epclusa), or sofosbuvir (Sovaldi) plus daclatasvir (Daklinza). All should be taken with ribavirin -- in some cases starting with a low 600 mg dose that can be increased if tolerated, for 12 weeks. While an 8-week treatment course is effective for many easier-to-treat patients, it is not advised for people with advanced disease.

Genotype 1 or 4 patients who are ineligible, unable, or unwilling to take ribavirin can use the DAAs alone and increase treatment duration to 24 weeks. Patients with prior sofosbuvir failure should both add ribavirin and extend therapy to 24 weeks.

For people with HCV genotypes 2 or 3, the AASLD/IDSA guidelines advise sofosbuvir/velpatasvir or sofosbuvir, daclatasvir, and ribavirin for 12 weeks. However, guidelines from the European Association for the Study of the Liver (EASL) recommend 24 weeks for patients with harder-to-treat genotype 3 disease.

Regimens containing paritaprevir (in the Viekira Pak, Viekira XR, and Technivie co-formulations), simeprevir (Olysio), or grazoprevir/elbasvir (Zepatier) are not recommended for patients with decompensated cirrhosis. Paritaprevir has been linked to worsening liver injury in people with advanced disease, and there are insufficient data on simeprevir and grazoprevir/elbasvir in this population, the guidelines state. Interferon-based regimens are no longer recommended for any HCV patients.

In the SOLAR-1 and SOLAR-2 trials, sofosbuvir/ledipasvir plus ribavirin for 12 or 24 weeks cured 85% to 89% of genotypes 1 and 4 patients with decompensated cirrhosis. About a third experienced serious adverse events, which were more frequent in people with more advanced disease.

The ASTRAL-4 study, which enrolled patients with all HCV genotypes, saw overall sustained virological response (SVR12) rates of 94% for sofosbuvir/velpatasvir plus ribavirin for 12 weeks and 86% for sofosbuvir/velpatasvir alone for 24 weeks. Genotype 1 patients did even better -- 96% and 92%, respectively -- but for genotype 3 cure rates fell to 85% for sofosbuvir/velpatasvir plus ribavirin and only 50% for sofosbuvir/velpatasvir alone.

In the smaller ALLY-1 study, sofosbuvir and daclatasvir plus ribavirin for 12 weeks cured 94% of Child-Pugh Class B patients -- similar to the SVR12 rate for people with compensated cirrhosis -- but just 56% of the sicker Class C patients.

While not matching the very high cure rates achieved by people with less severe liver disease, these DAA regimens are safer and far more effective than interferon-based therapy for people with decompensated cirrhosis, noted Chung. "The most important consideration in safely managing this group of patients is the degree of hepatic decompensation. In clinical trials, adverse outcomes of deterioration of hepatic function, while infrequent, occurred primarily in patients with the most advanced liver impairment."

Successful treatment can allow the liver to partially recover and is expected to reduce the risk of liver-related death over time. One recent study, for instance, found that curing HCV led to a reduction in portal hypertension.

"For those patients with more mild degrees of decompensation, clinical trials have repeatedly demonstrated that successful clearance of HCV can be associated with stabilization or even improvement of hepatic function. For some patients on liver transplant lists, clearance and clinical improvement has actually enabled successful removal from the list."

Clinical trials of DAA therapy showed that a majority of treated patients saw their Child-Pugh and MELD scores decrease, which raises questions about the optimal timing of therapy, Chung said.

In some cases successfully treated patients have enough improvement that they no longer need a transplant. A recent Italian study found that about a third of treated patients on a transplant waiting list had their status inactivated because of clinical improvement, and about two-thirds of those were eventually taken off the list entirely.

But in other cases treatment may improve liver function enough that patients fall to a lower priority on the transplant waiting list, but not enough that they no longer need a new liver -- a state dubbed "MELD purgatory."

The EASL guidelines address this dilemma, recommending that patients with less severe liver disease (MELD scores below 18-20) who are unlikely to receive a transplant within 6 months should be treated promptly. Those with higher MELD scores who can expect a donor liver sooner are advised to receive the transplant first and start treatment afterwards.

The best way for people with hepatitis C to avoid decompensation and the need for a transplant is prompt treatment, Chung emphasized. The AASLD/IDSA guidelines now recommend treatment for all, regardless of liver disease stage. As new therapies become more widely used, decompensation should become less common and liver transplant lists could shrink.

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